1. Technical Field
The present invention is a novel method (algorithm) for superposing the molecular structures of compounds for drugs, agricultural chemicals, etc., and it can be applied in the process of presuming active conformations from a number of metastable conformers. The invention is a novel superposing method (algorithm) for molecular structures of compounds utilizable for the presumption of active conformations on the compounds for drugs, agricultural chemicals, etc. and the creation of lead compounds for drugs, agricultural chemicals, etc. based on the three-dimensional structure data base searching.
2. Background Technologies
In the molecular designs of drugs, it is very important to determine the conformation of ligand molecule in the state of binding to proteins such as receptor and enzyme, that is, the active conformation thereof. For experimentally determining the active conformation of this ligand molecule, X-ray crystallography and NMR spectral analysis of the protein ligand complex have been known. However, it is accompanied with many difficulties that the crystallization of proteins such as receptor and enzyme is difficult, that enough quantity for analysis cannot be obtained, that molecular weight is too large to analyze, and the like. Hence, in computer assisted molecular designs, an approach is taken to presume the active conformation, based on the crystal structure of ligand molecule alone or the structure obtained from the calculation by molecular mechanics or molecular orbital method in a system that does not explicitly deal with the solvent molecules.
It has been considered that, even if the active conformation may not be the same as the most stable conformation obtained from the energy calculation, it comes to be a metastable conformation that is not so away, in view of energy. Moreover, it is also considered that the conformations of physiologically active peptide and some organic compounds in aqueous solution are close to the conformations in the state of binding to receptor and enzyme. In general, for the conformations of compounds binding to the same receptor and enzyme, a common feature that there is the same functional group in the same place in the three-dimensional space is considered, hence the superposition among functional groups of the metastable conformations is effective for the extraction of active conformation.
Based on this concept, the inventors provided a novel method for superposing molecular structures of compounds for drugs, agricultural chemicals, etc. in Japanese Unexamined Patent Publication No. Hei 10-298113. And, many inhibitor molecules in the state of binding to many enzymes were superposed, leading to the success in the reproduction of superposition obtained from X-ray crystallography. Furthermore, with respect to some inhibitor molecules, the inventors superposed among many metastable conformers and succeeded also in presuming the active conformations of inhibitor molecules in the state of binding to the enzyme (K. Iwase and S. Hirono, Journal of Computer-Aided Molecular Design, 13, 499-512, 1999). In the former, superpositions that cannot be presumed easily, such as superposition of elastase inhibitor TFK with TFA-Lys-Leu-ISO and superposition of 12 residues of OMTKY3 with Ace-Ala-Pro-Val-FPA were reproduced, and, in the latter, from superpositions of 113 conformers of NAPAP, 457 conformers of 4-TAPAP and 202 conformers of MQPA, the active conformations thereof were presumed, leading to the reconfirmation of the usefulness of superposing method provided in Japanese Unexamined Patent Publication No. Hei 10-298113. Here, the superposition obtained from X-ray crystallography means a superposition obtained by taking out inhibitor molecule's coordinates alone, after the least square fitting was performed among α carbon atoms on enzyme molecule's coordinates between enzyme-inhibitor complexes.
From the knowledge on structure-activity relationships and the like, many-compounds for drugs, agricultural chemicals, etc. having characteristic functional groups presumable to be concerned in the activity are known. In such cases, a superposing method that pays an attention to the characteristic functional groups common to compound molecules for drugs, agricultural chemicals, etc. is practical and necessary.